It has become common to treat a variety of medical conditions by introducing an implantable medical device partly or completely into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. For example, many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like.
For certain applications, the medical device is coated with a bioactive agent adapted to expose tissue within the body to the bioactive agent over a desired time interval, such as by releasing the bioactive agent. Desirably, the bioactive agent is released within the body at a reproducible and predictable fashion so as to optimize the benefit of the bioactive agent to the patient over the desired period of time.
Providing coated medical devices adapted to release a bioactive agent at a desired rate over a period of time is one challenge in designing implantable medical devices. For example, a coated medical device may release a bioactive agent at a greater rate than desired upon implantation, and subsequently release the bioactive agent at a slower rate than desired at some time after implantation. What is needed is a medical device that provides for release of one or more bioactive agents over a period of time that is desired for one or more bioactive applications, desirably at an optimal elution rate from the device.
Various approaches can be used to control the release of bioactive agents from an implantable medical device. The design configuration of an implantable device can be adapted to influence the release of a bioactive agent from the device. For example, a bioactive agent can be included in the implantable medical device according to various configurations. In some devices, the bioactive agent is contained within an implantable frame or coating on the surface of the implantable frame. An implantable frame may comprise a bioabsorbable material within or coated on the surface of the implantable frame, and the bioabsorbable material can optionally be mixed with a bioactive agent. Some implantable medical devices comprise an implantable frame with a porous biostable material optionally mixed with or coated on top of a bioactive agent. Implantable medical devices can also comprise a biostable material containing a removable material and a bioactive agent, where removal of the removable material forms pores that allow release of the bioactive agent.
The release of the bioactive agent may also be influenced by several factors, such as the molecular size of the polymer, the concentration of the agent in the polymer matrix, the glass transition point (Tg) of the polymer matrix, the crystallinity and solubility of the bioactive agent in various environments, the morphology of the coating and the thickness of the coating. A common release profile shows an initial release of a large amount of the agent (burst release), followed by a slow and gradual release leading to a plateauing effect.
There is a need for a medical device capable of releasing a bioactive agent over a desired time period, preferably as needed in the local area surrounding the site of medical intervention to promote a therapeutically desirable outcome. For example, it may be desirable for a medical device to provide a first rate of elution of the bioactive agent from an implanted medical device over an initial period of time and then a second rate of elution of the bioactive agent during a subsequent period of time. There is also a need for such a medical device capable of withstanding the flexion and impact that accompany the transportation and implantation of the device, for example by providing a high durability device coating adapted to deliver a bioactive agent within a body vessel.
An illustrative example involving the use of an implantable medical device is in the treatment of vascular disease. Bioactive agents can be applied to an implantable stent or valve to treat or mitigate undesirable vascular conditions such as restenosis or thrombosis formation. Procedures for mitigating such conditions may include implantation of a device comprising a bioactive agent.
For example, the implantation of stents during angioplasty procedures has substantially advanced the treatment of occluded body vessels. Angioplasty procedures may be employed to widen a narrowing or occlusion of a blood vessel by dilation with a balloon. Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as “restenosis.” Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. In addition, restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which involves the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded. To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed.
To reduce this problem, one or more bioactive agents may be administered to the patient. For example, a bioactive agent may be locally administered through a catheter positioned within the body vessel near the stent, or by coating the stent with the bioactive agent. One such bioactive is the antisense drug RESTEN-NG™ (NEUGENE® AVI Biopharma, Portland, Oreg.), which has applications in the treatment of restenosis in balloon injured coronary arteries. However, the delivery of water-soluble drugs, such as antisense drugs, presents particular problems. Such drugs are quickly eluted when subjected to an aqueous environment present within the body. As a result, such drugs can be eluted from a medical device prior to placement of the device or before an effective dose can be delivered at the target site.
Durable polymer drug carriers have been investigated for delivering water-soluble drugs. However, such polymers have the disadvantage of causing thrombosis and/or an inflammatory response over time. Although biodegradable polymers have been regarded as being more suitable drug carriers on medical devices, such as stents, those polymers currently used have not been effective for controlling the release of water-soluble drugs.